ALBERT

Description: Background: The paradigm for treatment selection in newly diagnosed (ND) multiple myeloma (MM) is largely predicated on establishment of suitability for front-line autologous stem cell transplantation. In this context, real-world evidence from multiple jurisdictions demonstrates that the most widely employed front-line (1L) therapies are bortezomib (B)-based triplets in transplant-eligible patients, and in transplant-ineligible patients, B-based triplets (or doublets) or the combination of lenalidomide and dexamethasone. While a sound hypothetical rationale for treatment stratification at diagnosis is recognised, viz alternative treatments for high-risk (HR) versus standard-risk disease, this is rarely employed in either everyday practice or clinical trials. A significant impediment to such an approach is the lack of a uniformly recognised risk stratification model that not only recognises truly HR disease (e.g. median survival from diagnosis 〈 24 months [m]) but is also accessible and affordable. Against this background we evaluated data from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) to define characteristics of 'functional' HR disease that could inform response-adaptive strategies, thus enabling the appropriate therapeutic targeting of HR patients. Methods: NDMM patients enrolled on to the MRDR since February 2013 with available data were evaluated. Patients were defined as either sub-optimal responders (SOR) to 1L if their best response was minimal response or stable disease (but not progressive disease [PD]), or early progressors (EP) if they demonstrated PD within 12m of commencing 1L therapy, irrespective of whether this occurred on or after the completion of 1L therapy. For categorical variables p-values were determined using a Pearson's chi-squared test, for continuous variables p-values were calculated using a Wilcoxon rank-sum test. Survival analysis was performed using the Kaplan-Meier method and p-values determined with the log-rank test. Results: 1320 NDMM patients were included with a median follow-up of 23m (12-37 IQR, 0-83 range). Of these, 152 were SOR (11.5%) and 118 were EP (8.9%). At diagnosis only 2 factors associated with SOR were identified: age 〉70y (p

Description: BACKGROUND & METHODS Cfz/Dex is a standard of care in relapsed MM, and renal impairment is a poor prognostic factor. The ALLG MM16 trial was initiated to assess the feasibility of treating patients (pts) who have significant RI (eGFR 15 - 40 ml/min) with Cfz/Dex, and to determine whether an early reduction in serum free light chains (SFLC), with a short half-life, could predict renal outcome. A pre-planned interim analysis was conducted after Cycle 1 of the 32nd registered pt, to assess disease and renal response, predictive value of early SFLC measurements and tolerability. Of concern was whether acute kidney injury (AKI) in the early stages of Cfz treatment may be more common in pts with RI. eGFR was calculated using the MDRD formula. SFLC was measured by the FreeLite assay. RESULTS Patient characteristics Mean age was 56.7 ±1 yr; Stage II/III: 4/28. Median eGFR at enrolment was 27 (IQR 21-32) ml/min. The first 11 pts received Cfz 20/27 mg/m2. After a safety analysis, the next 21 pts were treated at 20/56 mg/m2. Twelve pts were treatment naïve (TN) (all receiving 20/56) and 20 pts had relapsed MM (median 3 prior lines; range 1 - 8). One to 29 cycles were administered, median 4.5 in 20/27 and 4 in 20/56 group. Median follow up was 5.1 (0.1 - 26.5) months. Disease Response Of pts who received ≥4 cycles, 83% achieved ≥PR. In TN pts, best response rates were sCR 33%, CR 17%, VGPR 33%, PR 17%; in relapsed pts, CR 17%, VGPR 25%, PR 33%, PD 25%. Renal response After the first 2 cycles, 24% of pts had a complete renal response (IMWG criteria). To determine if Cfz acutely worsened eGFR, change in eGFR from baseline to day 7 (D7) and D28 was calculated. D7 eGFR showed substantial improvement in TN compared to relapsed pts (+5.6 vs -1.2 ml/min). At D28, the improvement in TN vs relapsed pts (+21.4 vs +3.5 ml/min), and in the 20/56 vs 20/27 group (+14.2 vs +3.5 ml/min) was more pronounced. Comparable results were seen in serum creatinine. Early free light chain kinetics Mean change in involved SFLC after 1 & 2 cycles were -54.5% and -67.0% respectively, with mean increase in eGFR of 9.3 and 11.4 ml/min. Involved LC reduction was significantly greater in 20/56 vs 20/27 doses (at C2D1, 81 vs 13%; p

Description: Treatment Of Acute Promyelocytic Leukemia (APML) In The Jehovah’s Witness (JW) Population. Colm Keane, Peter Mollee, Paula Marlton, Devinder Gill. Background: Treatment of acute myeloid leukaemia in JW patients is challenging. The refusal to accept blood products is usually a contraindication to intensive chemotherapy and a potential cure. Methods: We review three cases of APML occurring in JW patients treated at our institution which demonstrate the benefit of newer targeted combination therapies that induce less marrow suppression. Suggested management principles are derived from these anecdotal rare cases. Case 1 was a 39 year old male who was initially treated with ATRA (25 mg/m2) and Darbopoietin 100μg twice weekly with arsenic added on day 10 (0.15mg/kg/day). He initially tolerated therapy well despite severe pancytopenia until (day 20) the hemoglobin fell to 52g/L when he developed chest pain. He was diagnosed to have had a myocardial infarct in the setting of fluid retention. His WCC was 10.4 × 109/L with platelet count of 20 × 109/L. He was managed conservatively with no anticoagulation. His hemoglobin nadir was 44 g/L before rising above 80 g/L by day 38 of therapy at which time he was in cytogenetic and molecular remission. He completed a further 28 weeks of consolidation with ATRA (45mg/m2 for 2 weeks every 4 weeks) and arsenic (0.15mg/kg/day Mon-Fri, d1-28 every 2 months for 4 cycles). He has completed 9 months of planned 2 yrs oral maintenance chemotherapy (ATRA, 6MP, MTX) without further incident. Case 2 was a 62 year old female who was treated with ATRA induction (initially at 25mg/m2 but increased to 45mg/m2 on day 18), plus Erythropoietin (Epo) 4,000U × 3 per week s/c. She was in complete cytogenetic remission on day 37 and complete molecular remission by day 87. She had a hemoglobin nadir of 60 g/L but remained asymptomatic. Consolidation therapy commenced on day 106 consisting 3 cycles of combination therapy with ATRA (45mg/m2/d po for 4 weeks) and arsenic (0.15mg/m2/d iv for 5d/week for 4 weeks). Between consolidation cycles there was a 3-week interval during which all therapy was ceased. This regimen was well tolerated. She remains in complete remission after 8 years. Case 3 was a 28-year-old male who was initially treated with ATRA, low dose cytarabine and Epo 4000U 3-times/week s/c. He developed symptoms of severe anemia when his hemoglobin dropped to 25g/L with syncopal episodes and hypotension. He was subsequently found to have t (11:17) mutation and the leukemia did not respond to ATRA. He died from severe anemia fourteen days after presentation. Case reports published subsequently have shown that ATRA resistance in t(11:17) APML may occasionally be overcome if combined with standard chemotherapy or GCSF. However to date Arsenic has not been useful in this variant form of APML. Recommendations: Therapy. Induction with ATRA 25mg/m2 followed on day 10 by arsenic 0.15mg/kg/day until morphologic remission. Consolidation with alternating cycles of ATRA and arsenic as per Case 1. Maintenance therapy with ATRA, 6MP and MTX for 2 years. Anemia. Our patients tolerated severe anemia reasonably well until hemoglobin dropped to approximately 50g/L (most deaths in the literature due to anemia in the JW population have occurred below this threshold). All JW patients receive maximal erythropoietin stimulation and sparing phlebotomy episodes using paediatric blood collection tubes. Thrombocytopenia and coagulopathy. Antifibrinolytics, DDAVP and newer agents such as FVIIa have been used successfully in JW patients undergoing high risk surgery and may be of benefit in the APML setting for patients with haemorrhagic complications. Differentiation syndrome (DS) Case 1 may have developed DS. The standard management of DS is to commence chemotherapy such as idarubicin, cytarabine or gemtuzumab ozogamicin but because of the potential prolonged myelosuppression such agents are not suitable options for JW patients. We would advocate corticosteroids for DS prophylaxis and if treatment of DS is required, hydroxyurea may be a safer option because of its limited and shorter duration of myelosuppression. Conclusion: Our series demonstrates the benefit of more targeted therapy in APML allowing patients who refuse transfusion of blood products a realistic chance of cure.

Description: Background: ET carries a significant risk of thrombotic complications which are difficult to predict, with a past history of thrombosis being the main predictor of subsequent events. The JAK2V617F mutation (JAK2) and spontaneous erythroid colony growth (SEC) have been inconsistently associated with increased thrombosis in these patients. We aimed to assess the predictive value of these assays for the development of thrombotic events post-diagnosis in patients with ET. Methods: A retrospective review of consecutive patients with ET diagnosed according to WHO criteria between January 1998 and August 2006 was performed. Data was abstracted from the medical record regarding baseline demographic characteristic, vascular risk factors, therapy, occurrence of thrombo-haemorrhagic events, and transformation to AML or myelofibrosis. Thrombotic events were defined as arterial or venous events occurring at or 12 months prior to diagnosis (prior thrombosis) and at any time post diagnosis of ET (subsequent thrombosis). Investigators were blinded to JAK2 and SEC results at the time of data collection. SECs were performed at the time of diagnosis in 53 patients. JAK2 analysis was performed by an allele specific PCR method on peripheral whole blood (n=32) or archived bone marrow samples (n=29). Results: 62 patients with ET were identified: median age 60yrs; 53% female; median platelet count at diagnosis 873 × 109/L; 10,8 and 44 being low, intermediate and high clinical risk, respectively. 67% (41/61) had a positive JAK2 test and 47% (25/53) had a positive SEC assay. 8 (13%) and 6 (10%) had a history of prior arterial and venous thrombotic complications. Median follow up was 39 months (range, 1 to 137 months). At diagnosis JAK2 positive patients had higher white cell counts (12.3 vs 8.9 ×109/L, p=0.01) and neutrophil counts (9.1 vs 5.7 ×109/L, p=0.01), and a trend to older age (62 vs 57yrs, p=0.3) and higher haemoglobin (139 vs 133 g/L, p=0.12), but not platelet count (870 vs 892 ×109/L, p=0.8). There was a trend for increased rates of prior thrombosis among JAK2 positive patients (27% vs 5%, p=0.08). Survival was not affected by JAK2 status (5yr OS 71% vs 72%, p=0.7). The presence of the JAK2 mutation predicted for the development of subsequent thrombosis (5yr event rate 32% vs 0%, p=0.01) which persisted when the analysis was stratified for a prior history of thrombosis (p=0.01). Further analysis demonstrated the JAK2 mutation to predict subsequent arterial thrombosis (5yr event rate 22% vs 0%, p=0.05) but not venous thromboembolism (5yr event rate 11% vs 0%, p=0.18). The increased risk of arterial thrombosis in JAK2 positive patients persisted when corrected for a prior history of vascular events (p=0.04). The SEC assay was not found to be predictive of any thrombotic events. Conclusions: Patients with ET who are JAK2 positive are at increased risk of thrombotic complications, particularly arterial thrombosis. This increased risk persists after correction for a history of prior thrombosis.

Description: Introduction: The management of patients with treatment resistant AML (failure to achieve complete remission, CR; or CR with incomplete blood count recovery; CRi) after intensive chemotherapy is an important clinical consideration. Anticipating the benefit of intensive salvage therapy facilitates patient management decisions and counseling. The UK Medical Research Council (MRC) has associated morphologic partial remission (PRm; defined as 5-15% bone marrow blasts) after course 1 of standard-dose cytarabine (SDAC) based induction, with 5yr overall survival (OS) outcomes comparable to achieving CR (42 vs 51%). In contrast, failure to achieve PRm was linked to 5-year OS of 20% (Wheatley, et al 1999). In an MD Anderson study, patients failing initial high-dose cytarabine (HiDAC) based induction had a 6-month OS expectation of only 7% (Ravandi, et al 2010). Less than 1% of patients in this study achieved PR using International Working Group (IWG) criteria (treatment related decrease in marrow blasts to 5-25% with a 〉50% reduction from baseline and blood count recovery. We therefore sought to verify the prognostic relevance of PRm in patients with treatment resistant AML (no CR/CRi). Patients and treatment: A retrospective cohort of 104 patients failing intensive chemotherapy at 3 Australian hospitals (Alfred Hospital, Melbourne, Princess Alexandra and Royal Brisbane and Women's Hospitals, Brisbane) was identified. Prior therapy was standard-dose ara-C (SDAC) 100mg/m2 d1-7 in 73% or high-dose ara-C (HiDAC)(³1g/m2 cytarabine per dose for 5-8 doses) in 28% combined with idarubicin 9-12mg/m2 D1-3 as part of induction. For salvage after SDAC failure, the commonest regimens were HiDAC based, fludarabine and cytarabine (FLAG) variants or a second cycle of 7 + 3, the HiDAC group received further HiDAC based therapy, or FLAG based regimens. Outcomes were compared to a contemporaneously treated AML population (n=128) achieving CR/CRi. Results: OS was stratified according to the level of residual bone marrow blasts after induction. Patients with 5-15% residual blasts (PRm) had a median OS of 20.6 mo, compared to only 5.0 mo for patients with a residual blast count 〉15% (p

Description: Background: The PTLD-1 trial has demonstrated the efficacy and safety of 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF in CD20-positive PTLD after solid organ transplantation. Median overall survival (OS) was 6.6 years, a clear improvement over the preceding rituximab monotherapy trials (2.4 years). However, response to rituximab induction predicted OS after completion of therapy. Based on the hypothesis that rituximab consolidation might be sufficient treatment for patients already in a complete response (CR) after rituximab induction, trial treatment was changed in 2007 through a protocol amendment introducing risk-stratified sequential treatment (RSST): rituximab consolidation for patients in CR after rituximab induction and R-CHOP-21 consolidation for all others. Methods: In this international, multicenter phase II trial (PTLD-1, 3rd amendment; NCT00590447), treatment-naïve adult solid organ transplant recipients diagnosed with CD20-positive PTLD were treated with rituximab (375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, patients in CR continued with four three-weekly courses of rituximab monotherapy while all others received 4 cycles of R-CHOP-21 + G-CSF. In case of disease progression during rituximab monotherapy R-CHOP was commenced immediately. The primary endpoint was treatment efficacy measured as response rates and response duration. Analysis was by intention to treat. This is the final analysis of 152 patients treated with RSST from 2007 to 2014 at centers in Germany (72), Belgium (36), France (24), Australia (7), Poland (7) and Italy (6) with a median follow-up of 4.5 years. The 70 patients treated with rituximab followed by CHOP-21 in the original PTLD-1 trial (median follow-up 5.1 years) served as a control population. Inclusion criteria and follow-up schedule were identical; there were no significant differences in the transplant- and lymphoma-related baseline factors listed below. Results: 115/152 patients were male. 69/152 were kidney, 40 liver, 18 lung, 15 heart, 5 heart/kidney, 3 kidney/pancreas and 2 heart/lung transplant recipients. Median age at diagnosis was 56 years. PTLD was late (〉 1 year after transplantation) in 120/152 (79%) of patients. 67/145 (46%) PTLD were EBV-associated. 130/152 patients had monomorphic, 20 polymorphic and 2 early lesion PTLD. The overall response rate (ORR) was 111/126 (88%, CR: 88/126 [70%]). Median duration of remission (DR) was not reached; the 3-year Kaplan-Meier estimate was 82% (compared to 71% in PTLD-1). In the intention-to-treat population (152 patients), the median time to progression (TTP) was not reached either. The 3-year Kaplan-Meier estimate was 78% (69% in PTLD-1). Median OS by intention-to-treat was 6.6 years (95% CI 5.5 - 7.6) with a 3-year estimate of 70% in comparison to 61% in PTLD-1. There was no significant difference in ORR, DR, TTP or OS between EBV-positive and EBV-negative PTLD. On the other hand, response to 4 applications of rituximab was a highly significant predictor of OS, TTP and progression-free survival (PFS) despite treatment stratification (all p

Description: Abstract 1382 Poster Board I-404 Background: Central venous catheter-associated blood stream infections (CA-BSI) cause considerable morbidity in adult patients with hematologic cancers and solid tumors. A range of central venous access devices (CVAD) may be used across differing patient diagnoses and for varying indications. The aim of our study was to determine the incidence and risk factors for CA-BSI. Methods: A prospective observational cohort study of consecutive adult patients requiring a CVAD in a hematology-oncology unit (including autologous but not allogeneic transplantation) was performed. All CVADs were inserted under ultrasound guidance in a dedicated interventional radiology facility with peripherally inserted central venous catheters (PICCs) inserted in the basilic or cephalic vein and tunnelled lines, non-tunnelled lines and implantable ports inserted via the internal jugular vein. Standardized surveillance methods for CA-BSI were applied and data on CVAD complications were recorded. Results: 1119 CVADs were assessed in 723 patients over 50,478 line days. Median patient age was 55yrs and 56% were male. Patient diagnoses included aggressive hematologic malignancies (48%, includes AML (17%), MDS (1%), NHL (22%) and MM (8%)), Hodgkin lymphoma (3%), other hematologic malignancies (3%), oesophageal/colon/rectal cancers (26%), and all other solid tumors (20%). CVAD types included PICCs (71%), non-tunnelled lines (14%), tunnelled lines (14%), and implantable ports (1%). 291 lines were removed due to a clinical suspicion of infection, 133 of these had CA-BSI and 34 of these had a positive tip culture in addition to meeting the definition of CA-BSI. The four most common bacterial isolates were S. epidermidis (n=23), S. aureus (n=15), Pseudomonas sp (n=12) and Stenotrophomonas sp (n=10). The rate of CA-BSI per 1,000 line days was 2.63. In multivariate analysis, factors associated with CA-BSI included: type of CVAD (greatest for non-tunnelled lines (HR 3.67, p

Description: Background: Wilms’ tumour gene 1 (WT-1) is frequently over-expressed in adult AML and may be of prognostic value. We examined the prognostic utility of WT-1 expression in the peripheral blood, measured by RQ-PCR on diagnostic specimens, and characterised this compared to other clinical and biological predictors of survival. Methods: RQ-PCR was performed in triplicate on samples from newly diagnosed AML patients, using the Corbett Rotorgene 3000. Values were averaged and levels expressed relative to 104 ABL copies. Multivariate stratified Cox regression, with the stratification variable cytogenetic risk group and WT-1 levels analysed as a continuous variable, was used to model the outcomes of overall survival (OS) and event free survival (EFS). Results: Samples were collected from 58 patients with AML. The median age was 66 years (range 16–82) and 30 were male. Seven had antecedent haematological disorders and 9 had received prior chemo/radiotherapy. Induction therapy was with cytarabine based regimens in 18, high dose cytarabine regimens in 20, ATRA/chemotherapy in 6 and supportive care in 14. Complete remission was achieved in 64% with 18% induction mortality. Median OS was 4 months (17 months in responders) and 27% at 2 years. The median WT-1 transcript level in diagnostic AML samples was 5122 (range 9–36125), while in normal control samples it was 3 (n=11, mean 3.6, SD 1.6). In multivariate Cox regression, stratified by cytogenetic risk group, age (p

Description: Background: CBF AML, with t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) and the associated fusion proteins AML1/ETO or CBFβ/MYH11, has a favourable clinical prognosis although significant numbers of patients still relapse. We examined the prognostic utility of MRD monitoring by RQ-PCR and propose a simple model for prediction of impending haematological relapse. Methods: Patients with CBF AML had samples collected at diagnosis, after induction and consolidation chemotherapy and at routine regular intervals thereafter. RQ-PCR, using the Applied Biosystems 7700 Sequence Detection System, was performed in triplicate and the final result was calculated by averaging 3 values, expressed relative to PGK levels. Stratified Cox regression was used to assess the impact of predictor variables (diagnostic, post-induction, post-consolidation RQ-PCR levels and presence of a 1 log10 increase in sequential RQ-PCR levels) on leukaemia-free survival (LFS). Results: Of 46 patients identified with CBF AML, 29 had diagnostic, regular longitudinal samples and clinical follow up allowing further evaluation; 12 AML1-ETO and 17 CBFβ-MYH11. The median age was 39 years (range 7–68) with 52% male. Median follow up was 34 months (range 1–106) and median sample number was 6 (2–15). Twelve relapses occurred at a median of 11 months (range 4–17) from diagnosis. There were significant differences between transcript levels at diagnosis (median 1.9), post-induction (8.96*10−04), post-consolidation (5.01*10−05), in remission (1*10−06) or relapse (0.15) (p=0.01). Diagnostic, post-induction and post-consolidation RQ-PCR levels did not predict outcome. A log10 rise in a remission bone marrow sample correlated with adverse LFS and imminent risk of haematological relapse (HR 8.6). Relapses occurred a median of 60 days (range 45–272) after a log10 rise. RQ-PCR levels Hazard Ratio (HR) LFS 95% CI P-value Diagnosis 0.22 0.02–2.9 0.25 Post-induction 1.3 0.8–2.1 0.36 Post-consolidation 0.8 0.5–1.2 0.27 1 log10 increase 8.6 1.8–42 0.008 Conclusions: A 1 log10 rise in transcript levels was a highly significant predictor of haematological relapse. Transcript levels at early post-treatment time points did not predict long term outcome, cautioning against de-escalation protocols based on these results. Prospective identification of high risk patients will enable clinical trials to address the efficacy of treatment initiated at molecular progression.

Description: Introduction The optimal reduction of IST in renal transplant patients with PTLD is uncertain. As chemotherapy used to treat PTLD is inherently immunosuppressive, IST may be able to be stopped during this time without compromising graft function. Subsequent long-term reduction of IST is important to reduce PTLD relapse, but may increase long-term risk of graft rejection. Methods We performed a retrospective matched cohort study of adult renal transplant patients where IST was ceased during chemotherapy and then resumed at lower dose (calcineurin inhibitor at 50%, prednisolone